22-26451271-G-A

Position:

• chr22-26451271-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022081.6(HPS4):​c.*1962C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 152,046 control chromosomes in the GnomAD database, including 15,638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.45 (15638 hom., cov: 32)
• Consequence: HPS4 NM_022081.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.734

Genes affected

HPS4 (HGNC:15844): (HPS4 biogenesis of lysosomal organelles complex 3 subunit 2) This gene encodes a protein component of biogenesis of lysosome-related organelles complexes (BLOC). BLOC complexes are important for the formation of endosomal-lysosomal organelles such as melanosomes and platelet dense granules. Mutations in this gene result in subtype 4 of Hermansky-Pudlak syndrome, a form of albinism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 22-26451271-G-A is Benign according to our data. Variant chr22-26451271-G-A is described in ClinVar as [Benign]. Clinvar id is 903363.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS4	NM_022081.6	c.*1962C>T		3_prime_UTR_variant	14/14	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7	c.*1962C>T		3_prime_UTR_variant	14/14	1	NM_022081.6	ENSP00000381213	P2

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67905 AN: 151928 Hom.: 15641 Cov.: 32

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.477

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.447 AC: 67909 AN: 152046 Hom.: 15638 Cov.: 32 AF XY: 0.451 AC XY: 33525 AN XY: 74328

Gnomad4 AFR AF: 0.343

Gnomad4 AMR AF: 0.462

Gnomad4 ASJ AF: 0.557

Gnomad4 EAS AF: 0.486

Gnomad4 SAS AF: 0.387

Gnomad4 FIN AF: 0.588

Gnomad4 NFE AF: 0.479

Gnomad4 OTH AF: 0.470

Alfa AF: 0.463 Hom.: 2047

Bravo AF: 0.431

Asia WGS AF: 0.432 AC: 1502 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hermansky-Pudlak syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.51
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5761533; hg19: chr22-26847237;